Genetic Engineering in the Press by GEG

BCMA expression, copy number variation (CNV) and point mutations may have therapeutic implications for patients receiving CAR-T therapy or T cell engagers (TCEs) for multiple myeloma. Researchers performed whole genome sequencing (WGS) with 100x coverage on matched CD138-positive normal and tumour cells on 19 patients before BCMA TCE or CAR-T therapy and again at relapse. The researchers said they hoped to identify the extent to which antigenic loss of BCMA contributes to BCMA-targeted immunotherapeutic resistance. WGS identified a subclonal deletion of TNFRSF17 in 5% of patients before CAR T-cell therapy. The investigators then performed scCNV analysis on CD138-positive cells collected before and after treatment from relapsed multiple myeloma patients. Before anti-BCMA treatment, the researchers detected subclonal monoallelic copy number loss of TNFRSF17 in 14% of the tumour cells. In one patient who progressed from sustained complete remission on BCMA TCEs, the investigators observed an acquired monoallelic loss of BCMA coupled with a de novo non-truncating missense mutation in the TNFRSF17 extracellular domain at position 80, converting an arginine to proline at position 27. The investigators reported that this resulted in a measurable decrease in the area of BCMA expression.